Mycobacterium leprae


  • Acid-fast
  • Not grown in vitro; in the lab, it’s often grown in mouse footpads.
  • 14-day doubling time
  • Human pathogen
    — Has also been found in armadillos and some other non-human primates.
  • Route of transmission is not entirely established
    — Long-term contact is necessary.
    — It is thought that respiratory, and possibly skin secretions,transmit the bacteria.
  • Prefers cooler temperatures
    — Tends to infect superficial structures such as the skin and peripheral nerves
    — In some individuals, the anterior eye chambers and nasal cavities are also affected.
  • Long incubation period: typically between 3-10 years.
  • Intracellular pathogen
    — Macrophages and the Schwann cells of peripheral nerves.
    — In the histology image, we see foamy macrophages infected with Mycobacterium leprae
    — Schwann cell invasion causes demyelination and reduced conduction.
    — In the histology image, we see an example of a cutaneous nerve invaded by Mycobacterium leprae.


  • Chronic, typically non-fatal disease.
  • Major cause of peripheral neuropathy in areas where infection is endemic.
  • Treatment can include administration of dapsone, rifampicin, and clofazimine.
  • Be aware that Mycobacterium lepromatosis is also associated with Hansen’s disease; it causes diffuse lepromatous leprosy, and is endemic in Mexico and Costa Rica.

Infection produces a range of clinical manifestations

  • Disease severity is determined by the host’s cellular immune response, which is influenced by genetic components and environmental conditions.
  • Tuberculoid leprosy is the milder, less infectious form; Lepromatous leprosy is the more severe, disseminated, and infectious form; Borderline leprosy is in the middle, and is characterized as “immunologically unstable.”
  • Individuals move along this spectrum according to shifts in their immune system responses.

Be aware that there are additional clinically recognized stages that we have omitted for simplicity.

Tuberculoid leprosy

  • Associated with CD4+ T cell activation and type 1 cytokines, particularly IL-2 and interferon-gamma.
    — This produces an effective immune response that restricts infection.
    — Low bacillary load = Paucibacillary Hansen’s disease.
    — Negative slit-skin smear test
  • Tuberculoid leprosy is characterized by 5 or fewer lesions with granulomatous inflammation
    — Over time, inflammation damages the peripheral nerves.
    — Lesions are dry and scaly with irregular edges; the center of the lesions is typically hypo-pigmented.
  • Ultimately, nerve damage results in the loss of sensation; hair loss and reduced sweating ability can also occur.

Lepromatous leprosy

  • Associated with CD8+ T cells and type 2 cytokines, particularly IL-4 and IL-10.
  • This response produces an ineffective cellular immune response that facilitates disseminated infection.
  • High bacillary load = Multibacillary Hansen’s disease
  • Positive slit-skin test
  • Antibodies may be produced, but they form immune complexes that compound tissue damage.
  • Widespread lesions with thickened skin and nerve damage occurs.
    — Facies leonina, aka, lion face, is the result of thickened skin around the ears, nose, and brows with loss of the eyebrows and eyelashes.
    — Major nerves are commonly affected, including the median and ulnar nerves of the upper extremity, and the common fibular nerve and posterior tibial nerves of the lower extremity. The facial nerve is also often damaged.
    — Nerve damage can lead to muscular atrophy and paralysis.
    — Additionally, some patients experience testicular damage.

Leprosy reactions

  • Immune reactions with acute inflammation that can cause permanent nerve damage, so they need to be treated right away.
  • Analgesics can help with pain, and corticosteroids are necessary to suppress the immune system if nerve damage is suspected.

Type 1 Reactions

  • Associated with tuberculoid and lepromatous leprosy
  • Reversal reactions are caused by delayed hypersensitivityimmune responses
  • Edema and inflammation
  • Damage to the peripheral nerve trunks is a major concern.

Type 2 Reactions

  • Associated with lepromatous leprosy
  • Characterized by erythema nodosum leprosum that presents as subcutaneous nodules of inflammation on the extensor surfaces of the extremities.
  • Brought on by humoral immune responses that result in immune complex deposition.
  • Vasculitis and other complications that damage nerves and organs.
  • In patients where corticosteroids are contraindicated, thalidomide can be administered; however, this drug is associated with severe birth defects, so caution is warranted in women of child-bearing age.

Mycobacterium Tuberculosis Complex

General characteristics of Mycobacteria:

  • They have lipid-rich cell walls that are:
    — Acid-fast
    — Resistant to detergents and antibiotics
    — Contain antigens that stimulate the host immune response.
    — Layers:
  1. Cytoplasmic membrane
  2. Peptidoglycan layer – tends to stain weakly Gram-positive
  3. Arabinogalactan layer is a branched polysaccharide macromolecule that comprises arabinose and galactose residues; it links to the peptidoglycan layer, below.
  4. Mycolic acids, which comprises long-chain fatty acids; these acids contribute to the low permeability of Mycobacteria cell walls.

Be aware that some authors describe an outer capsule or capsule-like material.

  • Non-motile, non-spore-forming, aerobic, have high amounts of Guanine and Cytosine in their DNA, slow-growing, and most are weakly Gram-positive


  • Primary cause of tuberculosis
  • 18-hour doubling time
  • Produces non-pigmented colonies
    — We see this in the image of Mycobacterium tuberculosisgrown on Lowenstein-Jensen agar.
  • Cord factor (aka, trehalose dimycolate) is a lipid component of the cell wall that contains mycolic acids and gives virulent strains of Mycobacterium tuberculosis a “serpentine cord”arrangement.
  • Obligate human pathogens,
  • Humans are its only reservoir.
  • Transmitted in respiratory droplets, especially sputum produced by individuals with severe secondary pulmonary infections.
  • HIV-positive individuals and those with other cellular immunodeficiencies, including organ transplant recipients, are more susceptible to serious infection.
  • Intracellular pathogen
  • Virulence factors promote bacterial survival and replication in host cells:
    — Secretion systems and adhesins facilitate host cell invasion
    — Inhibition of phagosome-lysosome fusion allows the bacteria to avoid degradative lysosomal enzymes
    — Resistance to reactive oxygen species and nitric oxide, which are otherwise bactericidal
    — Prevention of cellular apoptosis, which allows the bacteria to replicate intracellularly; it is thought that, when the host cell is no longer useful, the bacteria promote necrosis, which facilitates their spread to new tissues and/or new hosts.
    — In summary, these virulence factors promote long-term survival of the pathogen; thus, tuberculosis is a disease of chronic inflammation.
  • Treatment for tuberculosis is complex, and involves long-term use of multiple antibiotics.
  • Detection:
    — Microscopy is a fast way to identify Mycobacteria by their acid-fast cell walls
    — Nucleic acid-based tests are then used to determine the specific species of Mycobacterium
    — Cultures taken from respiratory secretions can also be useful; however, remember that Mycobacteria have slow growth rates.
    — Molecular probes and mass spectrometry can be used to identify Mycobacteria.

Infection sites
Hematogenous or lymphatic spread of Mycobacterium tuberculosis can lead to disseminated infections or localized infections in specific organs. When the lesions are very tiny, this is called “Miliary tuberculosis.”

Pulmonary tuberculosis

  • The most common site of infection.
  • Characterized by granulomas and scarring; secondary infections can produce caseation and cavitation.
  • Symptoms include fever, night sweats, chest pain, coughing up blood, fatigue, and weight loss.
  • Pulmonary tuberculosis is often accompanied by infection of nearby lymph nodes.

Lymph nodes

  • Most commonly nodes in the cervical region
    — “Scrofula”
  • Infected nodes tend to be non-tender, firm, and discrete.
  • As infection progresses, nodes may form a mass of nodules.

Renal tuberculosis

  • Associated with renal transplants
  • Accounts for approximately 30% of extrapulmonary tuberculosis.
  • Patients often have sterile pyuria (elevated white blood cell count without evidence of bacterial growth) and microscopic hematuria.
  • Be aware that tuberculosis can spread through the urinary tract and to the genital tract.

Tuberculous osteomyelitis/arthritis

  • Most commonly effects the thoracic vertebrae, especially in children and young adults.
  • Spinal tuberculosis, aka, Pott’s disease, often produces Kyphosis or other deformities.

Gastrointestinal tuberculosis

  • Most often occurs after ingestion of contaminated milk or swallowed respiratory tract mucus.
  • Infection can involve the gastrointestinal tract, often where the ileum and cecum meet, as well as the peritoneum and abdominal lymph nodes.
  • Ulcerative lesions are common.

Erythema nodosum

  • Characterized by subcutaneous nodules on the anterior surface of the lower extremities.

Tuberculous meningitis

  • Most lethal form of infection.
  • Tends to affect young children and HIV-positive adults.
  • Associated with hyponatremia (low blood sodium concentration).


Mycobacterium bovis

  • Associated with cattle
  • Zoonotic infection when contaminated meat or unpasteurized milk is consumed.
  • Mycobacterium bovis bacillus Calmette-Guerin (BCG) is a derivation of Mycobacterium bovis
    — Used in a childhood vaccine to prevent some forms of tuberculosis infection.

Mycobacterium africanum

  • Tuberculosis-causing strain endemic to West Africa.


General Characteristics

  • Small, Gram-negative rods.
  • Visualized with Giemsa staining.
  • Lipo-polysaccharides in their membranes.
    – Weak endotoxin activity.
  • Specific Major Outer Membrane Proteins (MOMPS) that allow us to identify discrete serovars.
  • They are “energy parasites”
    – They rely on host cellular ATP.
  • Tropism:
    – Chlamydiaceae can enter non-ciliated columnar, cuboidal, and transitional epithelial cells.
    – Line the upper female reproductive tract, the urethra, the conjunctiva, and parts of the respiratory tract.
    – Thus, these are the sites of infection.

Unique developmental cycle
– Differentiate from elementary bodies, which are metabolically inactive infectious forms, to reticulate bodies,which are metabolically active noninfectious forms.

We show how this development cycle facilitates infection and destruction within host cells.

  • An infectious elementary body is ingested by the cell and contained within a phagosome.
  • Within the phagosome, the elementary body transforms to become a metabolically active reticulate body.
  • The reticulate body replicates via binary fission; the daughter cells reorganize into elementary bodies.
  • The phagosome containing both reticulate and elementary bodies is called an “inclusion body”
    – We can see examples of inclusion bodies in the histologic sample.
  • Within a couple of days, the host cell bursts, which releases elementary bodies that can then go on to infect new host cells.

Chlamydia trachomatis

  • Responsible for a range of infections.
  • Characterized by mucopurulent discharge characterizes these infections.
  • Treat with azithromycin, doxycycline, or erythromycin.
  • Trachoma is a chronic infection caused by Serovars A, B, and C
    – Transmitted via clothing, hands, and flies that move from person-person.
    – Infection leads to follicular conjunctivitis; scarring turns the eyelids and lashes inward.
    – Over time, the resulting abrasions can cause corneal scarring and pannus, leading to blindness.
    – Trachoma is endemic in areas of sub-Saharan Africa, the Middle East, and South Asia.
    – Children are predominantly affected.
  • Urogenital Infections are caused by Serovars D-K
    – The number one cause of sexually-transmitted urogenital infections in the United States.
    – Many women are asymptomatic, and, therefore, are key reservoirs; other women experience urethritis and/or inflammation of the reproductive tract (pelvic inflammatory disease, endometritis, etc.)
    – Most men are symptomatic and experience urethritis.
    – Co-infection with Neisseria gonorrheae is common.
    – Indicate that infection can provoke reactive arthritis, aka, Reiter syndrome, which is an autoimmune response characterized by arthritis, urethritis, conjunctivitis, and muco-cutaneous lesions.
    – Vertical transmission of Chlamydia trachomatis can lead to neonatal conjunctivitis or infant pneumonia; treatment of pregnant mothers can prevent transmission.
  • Inclusion conjunctivitis is an acute follicular conjunctivitis that can become chronic with scarring.
    – It is associated with urogenital infections.
  • Lymphogranuloma venereum is associated with Serovars L1, L2, and L3
    – This sexually transmitted infection is endemic in tropical and subtropical areas; sporadic outbreaks have been reported elsewhere.
    – The early stage is characterized by a localized lesion at the site of infection (typically the genitals or rectum); the lesion is painless, and heals spontaneously.
    – However, as infection moves to the lymph nodes, buboesform; show that they typically appear in the inguinal or femoral regions. Buboes can progress to fistulas that drain and/or rupture, and genital elephantitis can develop. Proctitis can also occur (inflammation of the anus and lining of the rectum).
    – Systemic symptoms of lymphogranuloma venereum include fever, chills, headache, and muscle and joint pains.

Chlamydophila pneumoniae

  • Causes mild to severe respiratory infections.
    – Atypical pneumonia may require hospitalization.
    – Macrolide administration is usually effective.

Chlamydophila psittaci

  • Associated with birds; thus, it is said to cause “Parrot fever.”
  • Infections can range from asymptomatic to severe, with pulmonary, hepatic, splenic, and other organ involvement.
  • Though rare, infection can lead to organ necrosis and hemorrhage, as well as airway obstruction.
  • Treatment includes doxycycline or macrolides.

Rickettsiaceae, Anaplasmataceae, & Coxiellaceae

  • Small, intracellular pathogens
  • Obligate aerobes
  • Gram-negative rods that stain best with Giemsa or Gimenez stains.
  • Some infections caused by these species are self-limiting
    • Doxycycline can be administered to shorten illness duration and prevent complications.

Species overview

Be aware that all of these species were formerly categorized as members of Rickettsiaceae, and that intertextual variation exists.

Rickettsiaceae damages endothelial cells of blood vessels

  • Rickettsia rickettsii causes Rocky Mountain Spotted Fever
  • Rickettsia akari causes rickettsial pox
  • Rickettsia prowazekii and Rickettsia typhi cause different forms of typhus
  • Orientia tsutsugamushi causes scrub typhus.
    to damage to the endothelial cells of blood vessels.


  • Ehrlichia chaffeensis causes human monocytic ehrlichiosis
  • Ehrlichia ewingii causes human ewingii ehrlichiosis
  • Anaplasma phagocytophilum causes human granulocytic anaplasmosis.


  • Coxiella burnetti causes Q fever.


Rickettsia rickettsii

  • Rocky Mountain Spotted Fever
    — Fever, headache, myalgias, and, sometimes, confusion (as a result of CNS involvement).
    — Patients commonly develop a macular rash that can progress to petechiae; the rash characteristically begins on the wrists and ankles, then spreads to the palms, soles, and trunk. This pattern of spread is a helpful distinguisher.
    — Gastrointestinal involvement is possible, and can cause abdominal pain, nausea, vomiting, and/or diarrhea.
    — Left untreated, disseminated vasculitis can lead to multi-organ failure.
  • Ticks and rodents are key reservoirs; hard ticks are vectors.

Rickettsia akari

  • Rickettsialpox
    — Typically less severe than Rocky Mountain Spotted Fever.
    — Patients experience fever and papulovesicular rash with eschars. Headaches and myalgia are possible.
    — Rodents are the reservoirs; mites are the vectors.

Rickettsia prowazekii

  • Epidemic typhus
    — Brill-Zinsser disease is the result of latent infection that manifests years, even decades, later.
    — Patients experience fever, headache, chills, myalgia, and a macular rash that spreads from the trunk to the extremities.
    — CNS involvement is possible, and can present as confusion.
    — If left untreated, vasculitis can lead to multi-organ failure.
    — Humans are the main reservoir, and the human body louse is the vector; be aware that flying squirrels and their fleas have also been described as reservoirs and vectors.

Rickettsii typhi

  • Endemic typhus (aka, murine, typhus)
    — Patients experience fever, headache, myalgia, and a maculopapular rash that spreads from the trunk to the extremities.
    — Gastrointestinal involvement is possible, and more common in children.
    — Cases are typically mild, but severe cases can lead to renal dysfunction or respiratory impairment (experienced as cough, dyspnea).
    — Small mammals, particularly cats and rodents, are key reservoirs; their fleas are the vectors.

Orientia tsutsugamushi

  • Scrub fever
    — Fever, intense headahces, mylagias, and a maculopapular rash that starts on the trunk; in some cases, eschars will form, especially at the site of inoculation.
    — Lymphadenopathy and pulmonary and neurologic involvement are common; gastrointestinal involvement may also occur.
    — Reservoirs include mites (chiggers) and rodents; mites are the vector.

Ehrlichia chaffeensis

  • Human monocytic ehrlichiosis
    — Fever, headache, and myalgia; Coughing is common in adults.
    — The rash associated with this infection varies, and is more common in children.
    — Central nervous system involvement is possible.
    — Leukopenia, thrombocytopenia, and elevated transanimases.
    — Deer, dogs, and other mammals are common reservoirs; soft ticks are the vector.

Anaplasma phagocytophilum

  • Granulocytic anaplasmosis
    — Similar symptoms and signs to human monocytic ehrlichiosis
    — Rash is rare.
    — Small mammals are the reservoirs; soft ticks are the vector.

Coxiella burnettii

  • Q fever
    — Fever, headache, and myalgia, but no rash.
    — Chronic Q fever can lead to serious complications, including hepatitis, pneumonia, and subacute endocarditis.
    — Reservoirs include mammals, ticks, and birds; though ticks are a potential vector, most cases of Q fever are the result of the aerosol inhalation or consumption of the bacteria in contaminated milk.

Overview of Gram-Negative Rods & Spirochetes – Febrile Illnesses & Rashes

  • Zoonotic illnesses, and most are transmitted via arthropod vectors.

Details and less common species can be found in separate tutorials.

Rash, Fever, & Headache

Rickettsia species:

  • Intracellular rods responsible for a range of illnesses.
  • Primarily target the lining of small vessels.


  • Rocky Mountain Spotted Fever
    – Bacteria are transmitted by hard ticks.
    – Infection produces a rash that begins on the hands and feet, then spreads to the trunk
    – Ocular involvement, such as conjunctivitis, is common.
    – Without treatment, widespread vascular damage can lead to organ failure and death.
  • Rickettsialpox
    – Bacteria that cause rickettsialpox are transmitted by mites.
    – Infection is characterized by an eschar, which is an area of redness with a blackish scab, at the site of the mite bite, and a vesiculopapular rash. The rash somewhat resembles the rash of chicken pox, which is why this illness is called “rickettsialpox”.
    – Infection is usually mild and self-limiting.
  • Epidemic typhus
    – Bacteria are transmitted via the human body louse.
    – Infection produces a pinkish macular rash that begin on the trunk and spreads to the extremities, and that the palms and soles are spared.
    Notice that this rash pattern is exactly the opposite that of Rocky Mountain Spotted Fever, which begins on the hands and feet and spreads to the trunk.
    – Widespread vascular damage can lead to death.
  • Brill-Zinsser disease occurs when latent infection re-emerges; it is typically less severe than the initial infection, and rash may be absent.
  • Endemic typhus, aka, Murine typhus
    – Bacteria are transmitted by fleas that parasitize small mammals, including cats.
    – Infection is similar to epidemic typhus, though usually milder.

Borrelia burgdorferi

  • Spirochete transmitted by hard ticks.
  • Causes Lyme Disease in the United States.
    – Other species of Borrelia are responsible for Lyme Disease outside the United States.
  • Lyme disease is a multi-system inflammatory disease.
    – Early stages are often, but not always, characterized by localized erythema migrans – which often looks like a “bulls eye”.
    Some patients also experience flu-like symptoms such as fever and headache.
    – Later, infection can produce multiple, but usually smaller, areas of erythema migrans.
    Bacteria can spread to multiple organ systems, notably, the nervous system, heart, and musculoskeletal structures.

Fever & Headache

Coxiella burnetti

  • Intracellular rods.
  • Not transmitted via arthropod vectors
  • Bacterial endospores are inhaled from animal hides or wastes.
  • Not everyone who inhales the endospores will get sick.
    – Some patients will develop Q fever, which presents with mild to severe flu-like symptoms.
    Severe cases can lead to pneumonia.
    Some patients develop hepatitis; Q fever hepatitis has a characteristic histopathology with fibrin ring granulomas that may or may not have fat vacuoles inside.
    – Chronic Q fever may develop later; endocarditis is a common complication.

Borrelia recurrentis and other Borrelia species

  • Species of Borrelia that cause relapsing fever are transmitted via body lice and soft ticks.
  • As its name suggests, relapsing fever is characterized by recurrent episodes of fever and septicemia, which are the result of bacterial proliferation.
    – Borrelia membrane proteins undergo antigenic variation, which promotes cycling between bacteremia and clearance.
  • We illustrate this cycle, as follows:
    – In response to bacteremia, host antibodies form and begin to clear the bacteria from the blood.
    – Bacteremia recedes, and the host enters the afebrile stage.
    – However, the bacteria rapidly undergo antigenic variation.
    – The new variants evade host antibodies and proliferate in the host.
    – Thus, the host enters a new febrile episode.
  • Symptoms of relapsing fever can range from mild to severe, and, in large part, depends on the causative species.
    – In addition to fever and headache, indicate that mild cases tend to produce muscle and joint pain, abdominal tenderness, and vomiting. Patients may also have jaundice and low platelet counts.
    – Severe cases can affect major organ systems and hepatic or cardiac failure or cerebral hemorrhaging.


  • Gastric helicobacter because it colonizes the stomach
  • Transmission is human to human; exact mechanisms uncertain.
  • Life-long colonization; infection typically occurs during childhood and produces symptoms during adulthood.
  • Gatalase, oxidase, and urease positive;
  • Spiral, Gram-negative rods that can appear as coccoid in older cultures.
  • Microaerobic: Grow in conditions of reduced oxygen and increased carbon dioxide.

Virulence factors

  • Helicobacter pylori has several adaptations that allow it to survive the acidic environment of the human stomach and persist for decades.
  • Urease converts urea to ammonia and bicarbonate to neutralize gastric acids.
  • Multiple flagella provide corkscrew motility
  • Mucinase production allows the bacteria migrate through the viscous mucus that covers the surface of the stomach.
  • Infection triggers host production of IL-8, which is a pro-inflammatory cytokine that recruits neutrophils that release harmful molecules and damage host tissues.
  • The bacteria protect themselves from these harmful molecules by producing superoxide dismutase and catalase, which detoxify reactive oxygen species.
  • Lipopolysaccharide endotoxin; however, as compared with many other Gram-negative bacteria, its endotoxin has low toxicity.
  • Vacuolating cytotoxin A promotes pore formation, disrupts cell signaling, and induces apoptosis and necrosis of host cells.
  • Cytotoxin-associated gene A (cagA) product promotes proliferation and morphological changes in host tissues, and induces T-cell  apoptosis.
    – Type IV secretion systems* inject the cagA effector protein into host cells.


  • Gastritis is inflammation of the stomach lining with infiltration of neutrophils and mononuclear cells; T-1 helper cells are also implicated.
    – Some individuals are asymptomatic, and others experience an acute phase of nausea, bloating, and vomiting.
    – Inflammation can be localized to one area, usually the pyloric antrum, or widespread
    – In a subset of patients, gastritis progresses to more serious conditions.
  • Peptic ulcers
    – 10-20% of patients with gastritis will develop peptic ulcers, in which inflammation erodes the stomach tissues.
    – Ulcers can be located in the stomach, or they can be in the duodenum, which is the first portion of the small intestine.
  • Gastric adenocarcinoma
    – In approximately 1-2%, chronic inflammation will lead to gastric adenocarcinoma.
    – This occurs when inflammation leads to metaplasia; over time, the gastric mucosa is replaced by fibrotic tissue, and can become neoplastic.
    – Reduced gastric acid secretion is associated with a higher risk of adenocarcinoma.
  • Gastric-associated lymphoid tissue B-cell lymphomas
  • In response to Helicobacter pylori infection, lymphoid tissues infiltrate the stomach; in some cases, monoclonal B cells proliferate and form MALT lymphomas (MALT = Mucosa-Associated Lymphoid Tissue).

Summary Illustration:

We draw the stomach, esophagus, and duodenum.

Gastritis can be localized in the pyloric antrum, and indicate that this is associated with increased acid production and formation of duodenal ulcers.

  • Multifocal inflammation, as in pangastritis, is associated with atrophy and reduced acid production; this is associated with gastric metaplasia and cancer.
  • Helicobacter pylori infection causes destruction of the mucosa, which allows acids and toxins, as well as the microbes themselves, access to deeper tissues.
  • Ulceration leads to bleeding, perforation, and, in severe cases, metaplasia.


Because chronic gastritis can lead to severe consequences, treatment is important.

  • Macrolides, Beta-lactams, and proton-pump inhibitors.

Enterohepatic helicobacters

Helicobacter cinaedi and Helicobacter fenneliae

  • Invade the intestines and liver, and can cause gastroenteritis and bacteremia, particularly in immunocompromised individuals.


  • Spiral, gram-negative rods; may appear coccoid in older cultures.
  • Generally heat-resistant, and are cultured at 42 degrees Celsius (note that Campylobacter upsaliensis is an exception).
  • Grow in microaerobic conditions with relatively low oxygen levels and elevated carbon dioxide.
  • Oxidase positive.
  • Tiny, so they can be filtered from stool samples for diagnostic purposes.
  • Vulnerable to stomach acids; thus, illness is most common in individuals with reduced stomach acid production.
  • Zoonotic infections; that is, illness occurs after interactions with colonized animals.

Virulence factors:

  • Lipo-oligosaccharide endotoxin.
  • Polysaccharide capsule.
  • Flagella facilitate motility and invasion of host cells.
  • Cytolethal distending toxin is thought to cause cell death and IL-8 secretion. IL-8 is a pro-inflammatory cytokine that, when produced in excess, damages host tissues.


Campylobacter species are the number one cause of bacterial gastroenteritis in the United States.

  • Gastroenteritis is characterized by watery, sometimes bloody, diarrhea with blood cells present in the stools; some individuals have fever.
  • Fortunately, the diarrhea is usually self-limited; illness lasts approximately six days.
  • In severe cases, or where complications arise, erythromycin or azithromycin can be administered.

Campylobacter jejuni

  • Primary pathogenic species; infection is associated with consumption of contaminated poultry and cow products.
  • Damages the mucosa of the jejunum, ileum, and colon.
    – Villus ulceration (can become bloody)
    – Neutrophils, eosinophils, and mononuclear cells invade the lamina propria
    – Abscesses form in the glands and crypts.
  • Infection can also cause bacteremia and cardiovascular dysfunction.

Post-infection complications:

  • Guillan-Barré syndrome is an autoimmune disorder that damages the myelin of the peripheral nervous system (hence it’s a demyelinating disorder).
  • Individuals typically experience symmetrical weakness that begins in the lower extremities; weakness may ascend, and, in severe cases, can impair cardiovascular and respiratory functioning due to autonomic system involvement.
    – Blood pressure can swing wildly, so clinicians must be careful not to react too quickly to spikes in blood pressure or they can inadvertently cause devastating low blood pressures.
    – Indicate that early treatment with IVIG or plasmapheresis is important in management but most important is good supportive care while the illness runs its course, meaning early intubation, if respiratory distress is identified, and good nursing care to avoid superimposed infections.
  • Keys to diagnosing the disorder are:
    – Hyporeflexia (from the peripheral neuropathy).
    – CSF findings of cytoalbuminologic dissociation (meaning normal WBC but elevated protein)
    – EMG findings that may be normal early on but later show prolonged F Waves, conduction block, and eventually the demyelination (prolonged distal latencies and conduction velocities).
  • Campylobacter jejuni infection, itself, is associated with a particularly aggressive form of Guillain-Barre, called Acute Motor Axonal Neuropathy (AMAN) (it’s most common in China and Japan).
    – This variant actually affects the axons, themselves, rather than simply disruption of the myelin-coating of the nerve – and thus will demonstrate as an axonopathy on EMG.
  • Reactive arthritis is typically characterized by joint swelling and pain in the hands, knees, and ankles.

Campylobacter coli infection is associated with consumption of contaminated pork and poultry products.

  • It primarily causes gastroenteritis, but is also associated with some extra-intestinal infections.

Campylobacter upsaliensis is an emerging pathogen associated with cats and dogs; thus, outbreaks have been traced to pet stores.

  • It primarily causes gastroenteritis.
  • Has been associated with Guillain-Barré syndrome.

Campylobacter fetus

  • Infection primarily occurs in immunocompromised individuals.
  • Resistant to serum killing by antibodies and complement, thanks to the presence of S protein, which prevents C3b binding.
  • Bacteremia and septic thrombophlebitis (venous thrombosis with bacteremia)
  • Endocarditis
  • Meningoencephalitis
  • Gastroenteritis

Be aware that this species was originally named Vibrio fetus.

Vibrio cholerae, Vibrio parahaemolyticus, & Vibrio vulnificus


  • Gram-negative rods.
  • Facultatively anaerobic
  • Oxidase-positive
  • Polar flagella facilitate rapid motility.
  • Found in water, especially estuaries and coastal waters, because salt is required for growth.
  • Upon ingestion, pathogenic strains cause gastrointestinal disease.


Causative agent of cholera.

  • Ingested as free-living cells, micro-colonies, or as biofilms in contaminated foods or water.
  • Sensitive to stomach acids
    – Infection typically requires exposure to a large quantity.
    – However, individuals with impaired stomach acid production are vulnerable to lower infectious doses.
  • Gastroenteritis caused by Vibrio cholerae causes mild to severe vomiting and watery diarrhea
    – In severe cases, the profuse stool has a characteristic milky-white “rice water” appearance.
  • Proper sanitation and thorough cooking of food can prevent cholera epidemics.
    – Vaccination can help prevent worsening conditions in areas where cholera is endemic.
  • Infected patients should be given antibiotics, such as tetracycline, to avoid dehydration and death.

Cholera epidemics: Vibrio cholerae O1 and O139

  • Vibrio cholerae O1 is further subdivided into biotypes and serotypes.
    – Biotypes: Classical and El tor
    – Serotypes: Ogawa and Inaba; Hikojima is thought to be a hybrid transitional state.
  • Severe fluid loss leads to dehydration, which can result in metabolic acidosis, hypokalemia, hypovolemic shock, cardiac arrhythmia, and renal failure.
  • Cholera is endemic in some parts of the world; asymptomatic carriers contribute to its maintained presence.
  • Cholera outbreaks occur in areas where humanitarian and/or environmental crises lead to overcrowding and poor sanitation.

We show how Vibrio cholerae O1 and O139 acquire the virulence factors that promote severe gastroenteritis.
– Horizontal gene transfer is key to this process.

  • First, we draw a couple of small intestine epithelial cells and indicate the intestinal lumen.
  • Then, we draw a non-pathogenic Vibrio cholerae bacterium.
    – Its chromosomal DNA has already acquired Vibrio Pathogenicity Island -1 (VPI-1), which carries genes for Toxin co-regulated pili.
  • Toxin co-regulated pilus is a type of bundle-forming pilus that promotes microcolony formation, which is important for Vibrio cholerae colonization.
  • This pilus is also a receptor for bacteriophage CTXφ, which injects DNA into the V. cholerae microbe.
    – Without the pathogenicity island and toxin co-regulated pilus, the bacteriophage would not be able to attach to the microbe and transfer DNA.
  • Next, we show that the CTX prophage has been integrated into the chromosomal DNA.
  • The CTX prophage triggers production of cholera toxin,
    – Cholera toxin interacts with binding sites on the small intestine epithelial cells.
  • Cholera toxin increases cyclic AMP, which leads to water and electrolyte secretion into the lumen.
    – Profuse watery diarrhea ensues.
  • The CTXφ prophage also carries genes for two additional toxins:
    – Accessory cholera enterotoxin (ACE) contributes to water and ion secretion; some authors report that this enterotoxin, alone, can induce gastroenteritis.
    – Zona occludens toxin (ZOT) disassembles epithelial tight junctions, which increases intestinal permeability.
  • Neuraminidase increases the availability of cholera toxin binding sites on host cells
    – The nanH gene that codes for this enzyme is carried separately.

Non-O1 and non-O139 Vibrio cholerae strains can cause mild diarrhea.

Virulence factors of these strains vary.

  • Non-O1 strains have polysaccharide capsules that facilitate spread beyond the intestine.
  • Various toxins, including heat-stable enterotoxin, induce diarrheal symptoms.


Associated with gastroenteritis, septicemia, and wound infections.

Vibrio parahaemolyticus

  • Lives as free cells in contaminated food and water;
  • Halophilic
    – “Salt-loving;” growth on most media requires the addition of sodium chloride.
  • Virulence factors:
    – Type three secretion systems inject protein effectors into host cells.
    – Thermostable Direct Hemolysin (TDH) and TDH-Related Hemolysin (TRH) are enterotoxins that increase intestinal fluid secretion; they also act as cytotoxins that affect other host cells.

Thermostable direct hemolysins produce beta hemolytic halos when grown on Wagastuma blood agar; this is called the Kanagawa phenomenon. However, be aware that strains carrying only the TDH-related hemolysin (TRH) gene are Kanagawa phenomenon-negative, but can still cause gastroenteritis. Thus, the absence of beta hemolysis does not necessarily mean that the strain is non-pathogenic.

  • Plastic motility:
    – With a single flagellum, it moves as a rapid swimmer cell
    – In more viscous environments, the microbe produces multiple lateral flagella and moves as a swarmer cell.
  • Capsule synthesis is also up- or down-regulated in response to environmental changes.

Vibrio vulnificus

  • Associated with warm saltwater.
  • Halophilic.
  • Ferments lactose, which can aid in its identification.
  • Strains can be further classified into three biotypes.
  • More likely to cause infections in males; it has been suggested that estrogen has protective effects.
  • Individuals with elevated free iron levels are also more susceptible to infection, likely because Vibrio vulnificus thrives in iron-rich environments.
  • Overall, Vibrio vulnificus is responsible for most sea-food related deaths in the U.S.
  • Virulence factors:
    – A polysaccharide capsule protects from host immune responses
    – Proteases break down host tissues
    – Hemolysins release iron from host storage
    – Cytolysins cause cell death
    – Endotoxin comprises LPS; triggers cytokine release.

V. parahaemolyticus & V. vulnificus Infections

Infection is more common in individuals with immunodeficiencies and/or liver disease, which is associated with decreased neutrophil activity.

Self-limiting Gastroenteritis is associated with consumption of raw oysters that are contaminated with Vibrio parahaemolyticus.

  • Vibrio parahaemolyticus is associated with more than half of all cases of seafood-borne bacterial gastroenteritis.
  • Results from consumption of shellfish, especially raw oysters.
  • Symptoms include watery diarrhea, abdominal cramps, nausea, vomiting, headache, and fever.
  • Fortunately, gastroenteritis is preventable by cooking, which kills the bacteria.
  • In most cases, gastroenteritis is self-limiting.

Septicemia is associated with consumption of raw oysters that are contaminated with Vibrio vulnificus

  • In the bloodstream, Vibrio vulnificus triggers a systemic inflammatory response; the bacteria are protected their polysaccharide capsules, but massive release of pro-inflammatory cytokines damages the host.
  • Gastrointestinal symptoms followed by chills, fever, and septic shock are associated with septicemia.
  • The mortality rate is high; in some reports, more than half of infected patients die.
  • Antibiotics

Wound infections

  • Occur after exposure to contaminated water.
  • Mild infections can lead to cellulitis; this is more common when Vibrio parahaemolyticus is the causative agent.
  • Severe cases can lead to necrotizing fasciitis; this is more common when the wound is infected by Vibrio vulnificus.
  • Treatment includes antibiotic administration; if necrotic tissue is present, surgical debridement is also necessary.

Overview of Gram-Negative Rods – Gastrointestinal illness (non-enterobacteriaceae)

Helicobacter pylori

  • Spiral rod-shaped bacterium; it can appear coccoid in older samples.
  • Very common pathogen; present in about half the world’s population.
  • Colonization is life-long; introduction often occurs during childhood, though symptoms of infection occur later in adulthood.
  • Bacterial carcinogen.
  • Gastritis
    – Inflammation of the stomach lining.
    – Inflammation can be localized or widespread, and can affect the duodenum.
    – Neutrophils infiltrate the mucosa.
  • Peptic ulcers
    – Bacteria erode the mucosal lining of the stomach and/or duodenal.
  • Gastric adenocarcinoma
    – Associated with chronic, widespread inflammation.
    – Mucosal tissue is replaced by fibrous tissue and intestinal–type epithelium.
  • Gastric mucosa-associated lymphoid tissue B-cell lymphomas
    – B-cells migrate to the stomach mucosa and establish lymphomas.


  • Common causes of bacterial gastroenteritis.
    – Also cause extra-intestinal infections.
  • Spiral rod-shaped but may appear coccoid in older specimens.
  • Campylobacter jejuni
    – Distinct histopathology, with ulcerated and bloody villi, white blood cell infiltration, and the formation of abscesses in the intestinal glands and crypts.
  • In some individuals, Campylobacter jejuni infection triggers immune-mediated disorders.
    – Guillain-Barré syndrome occurs when the immune system targets the peripheral nervous system.
    Patients experience tingling and ascending weakness; ultimately, impairment of inspiratory muscles can lead to respiratory failure.
    – Reactive arthritis is characterized by joint pain and swelling.

Vibrio cholerae and Vibrio parahaemolyticus

Vibrio parahaemolyticus is also associated with wound infections.

  • Consumed in contaminated food or water.
  • Gastroenteritis caused by Vibrio species is characterized by watery diarrhea, cramps, vomiting, and nausea.
  • Choleara
    – Two strains of Vibrio cholerae are associated with cholera, which is a severe gastroenteritis that produces profuse watery diarrhea (sometimes referred to as “rice water” diarrhea).
    – If untreated, Cholera can lead to fatal dehydration.

Miscellaneous Gram-Negative Rods (Bartonella, Bordetella, Brucella, & Legionella)


  • Transmitted to humans via insect vectors.

Bartonella bacilliformis causes Carrión disease, primarily in the Andes mountains.

  • 1st phase of infection: Oroya fever
    – Acute hemolytic bacteremia with fever and anemia.
    – Can be fatal.
  • 2nd phase: Chronic verruga peruana (Peruvian warts)
    – Blood-filled cutaneous nodules.
  • Treat with chloramphenicol or ciprofloxacin.

Bartonella quintana is transmitted in louse feces;

  • Trench fever, which is also referred to as “5-day fever” because of recurring fever with headache, weakness, and pain in the long bones, particularly the tibia.
  • Immunocompromised individuals can develop bacteremia with myalgia, malaise, weight loss, fever, and headache.
    – Bacteremia can lead to subacute endocarditis or bacillary angiomatosis, which is characterized by neovascular proliferation and formation of blood-filled nodules in the skin, subcutaneous tissues, and bones.

Bartonella henselae is transmitted by cats and their fleas.

  • Cat-scratch disease typically presents as lymphadenopathy; however, infection can become disseminated.
  • Bacillary angiomatosis of the skin, lymph nodes, spleen, and liver.
  • Subacute endocarditis


Causes pertussis, aka, whooping cough.

  • Childhood vaccine DTaP (Diphtheria, Tetanus, and Pertussis) and “booster” vaccines prevent pertussis.
    Bordetella pertussis and Bordetella parapertussisBordetella pertussis causes the more severe form of illness.
  • Pertussis is most severe in infants, in whom it can lead to respiratory failure.
  • Cases of adolescent and adult pertussis are on the rise; these populations are reservoirs for the bacteria.
  • Stages of Pertussis
    – 7-10-day incubation period
    – Catarrhal stage: 1-2 weeks of symptoms that resemble the common cold.
    – Paroxysmal stage: 1-10 weeks of forceful coughing fits followed by inspiratory gasps – the “whooping” sound. Post-tussive vomiting is common.
    – Convalescence stage: Coughing is reduced, but serious complications may occur. Pertussis is associated with the development of pneumonia, seizures, apnea, and encephalopathy.

Virulence factors of Bordetella pertussis

Facilitate invasion and destruction of the respiratory tract.

  • Adhesins, including filamentous hemagglutinin and fimbriae.
  • Adenylate cyclase toxin blocks phagocytosis and prevents T-cellactivation.
  • Dermonecrotic toxin forms necrotic lesions in the tissues.
  • Tracheal cytotoxin destroys ciliated cells of the respiratory tract.
  • Pertussis toxin increases cyclic AMP, promotes leukocytosis, and suppresses the host immune response
    – Secreted via Type IV secretion systems.


The number one cause of bacterial zoonotic infections worldwide.

  • Brucella bacteria are associated with livestock; epidemics among farm animals lead to economic devastation.

Brucella melitensis, Brucella abortus and Brucella suis

Brucella melitensis is associated with most human infections.

  • Intracellular pathogens that cause chronic infections with granuloma formation, particularly in the reticuloendothelial system.
  • Treatment includes doxycline and streptomycin or rifampin; relapse is common.
  • Brucellosis mimics other infectious diseases; because of this, diagnosis is often delayed.


  • Early infection is characterized by undulant fever with chills, sweating, coughing, vomiting, and weakness.
  • Advanced infection is systemic with multi-organ effects and increased risk of abortion.


  • Associated with rabbits, ticks, and flies.
  • Intracellular pathogen.


  • Ulceroglandular tularemia is most common manifestation.
    – Characterized by localized ulcers and glandular swellings.
  • Glandular tularemia produces glandular swellings.
  • Oculoglandular tularemia
  • Oropharyngeal infections
  • Pneumonic tularemia can be fatal.
  • Treatment is gentamicin.


  • Found in water, including natural bodies of water, spas, air conditioners, and water misters.

Legionnaires disease

  • Severe pneumonia with consolidation, as well as multi-organ damage.
  • Treatment involves Macrolides

Pontaic fever

  • Less severe than Legionnaires disease
  • Fu-like symptoms, including fever, chills, myalgia, malaise, and headache.
  • Antibiotic treatment is unnecessary in most cases, because the illness is self-limiting.